2-Amino-2- acetonitrile synthesis

The synthesis of 1,2,5-thiadiazoles from amino acetonitrile salts 172 was reviewed in CHEC-II(1996). Owing to the ready formation of 2-amino acetonitrile salts from aldehydes via a one-pot Strecker synthesis, this synthetic pathway... 

In its utilization of acetonitrile, the oxazoline synthesis shown in Scheme 56 resembles a Ritter reaction.The procedure is convenient, but yields are variable the pyrolysis gives starting alkene plus acetamide as by-products. Another oxazoline synthesis and subsequent conversion to a cif-amino alcohol is discussed later (Scheme 85). A recent y-hydroxy-a-amino acid synthesis incorporates the following type of transformation (Scheme 57).If a three-day equilibration with anhydrous HBr was introduced iMtween stages i and ii, almost pure trans product was obtained. The paper has many usefol references. Yet another modified Ritter reaction is shown in Scheme 58. ... 

In an acetonitrile suspension, the intermediate a-cyanoalkoxide can be trapped by acyl chlorides to give cyanohydrin esters. In a preparation of synthetic pyrethroids, the comparison between the sonicated reaction and its PTC equivalent gave an advantage to the latter in terms of reaction time and yield. i A modest change in stereoselectivity is observed in some cases. The same reaction in the presence of ammonium chloride leads to a-amino nitriles, the first step of the Strecker amino acid synthesis.4 72 xhe procedure is more efficient in the presence of alumina. The formation of by-products, cyanohydrins or benzoins, is avoided. From an experimental viewpoint, the work-up is considerably easier than with conventional procedures, and consists mostly of a simple filtration. With ketones, and in the presence of ammonium carbonate, a hydantoin is formed (Eq. 21)7 ... 

Miscellaneous Transformations. Cyanotrimethylsilane effects the transformation of acyl chlorides to acyl cyanides, a-chloro ethers and a-chloro thioethers to a-cyano ethers and a-cyano thioethers (eq 19), t-butyl chlorides to nitriles (eqs 20 and 21), 1,3,5-trisubstituted hexahydro-l,3,5-triazines to amino-acetonitriles, the cyanation of allylic carbonates and acetates (eqs 22 and 23), and the formation of aryl thiocyanates from aryl sulfonyl chlorides and sulfinates. The reagent has been used effectively in peptide synthesis and in a range of other synthetic applications. " ... 

Hydrogenation reduces the nitro group to amino which is then diazotized using sodium nitrite and tetrafluoroboric acid. The diazotized crown was not isolated but the aq. solution was treated directly with sodium acetate and bis(dibenzylideneacetone)-pal-ladium(O) in acetonitrile solution. Ethylene was then introduced to the autoclave and the solution was allowed to stir for 2 days. 4 -Vinylbenzo-15-crown-5 was isolated (30% from 4 -nitrobenzo-15-crown-5) as a colorless solid (mp 43.5—44.2°) °. The synthesis is illustrated in Eq. (3.16). 

In the 3-adrenergic blocking drug pyrroxan (48), the catechol moiety is masked in a doxane ring. The synthesis begins by alkylation of phenyl acetonitrile by 2-chloroethanol to produce alcohol Recuction converts this to amino alcohol which... 

The synthesis of the E-ring intermediate 20 commences with the methyl ester of enantiomerically pure L-serine hydrochloride (22) (see Scheme 9). The primary amino group of 22 can be alkylated in a straightforward manner by treatment with acetaldehyde, followed by reduction of the intermediate imine with sodium borohydride (see 22 —> 51). The primary hydroxyl and secondary amino groups in 51 are affixed to adjacent carbon atoms. By virtue of this close spatial relationship, it seemed reasonable to expect that the simultaneous protection of these two functions in the form of an oxazolidi-none ring could be achieved. Indeed, treatment of 51 with l,l -car-bonyldiimidazole in refluxing acetonitrile, followed by partial reduction of the methoxycarbonyl function with one equivalent of Dibal-H provides oxazolidinone aldehyde 52. 

The method is very useful for the synthesis of physiologically interesting a-mcthylamino acids, e.g., methyl dopa from the 3,4-dimethoxybenzyl derivative. The excellent stereoselection achieved in the process, however, is caused by the preferential crystallization of one pure diastereomerfrom the equilibrium mixture formed in the reversible Strecker reaction. Thus, the pure diastcrcomers with benzyl substituents, dissolved in chloroform or acetonitrile, give equilibrium mixtures of both diastereomers in a ratio of about 7 347. This effect has also been found for other s-methylamino nitriles of quite different structure49. If the amino nitrile (R1 = Bn) is synthesized in acetonitrile solution, the diastereomers do not crystallize while immediate hydrolysis indicates a ratio of the diastereomeric amino nitriles (S)I(R) of 86 1447. 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

A thio-Claisen rearrangement174 was used for the regioselective synthesis of thiopyrano[2,3-b]pyran-2-ones and thieno[2,3-b]pyran-2-ones (Eq. 12.76). A convenient method for the aromatic amino-Claisen rearrangement of N-(l,l-disubstituted-allyl)anilines led to the 2-allylanilines being produced cleanly and in high yield by using a catalytic amount of p-toluenesulfonic acid in acetonitrile/water (Eq. 12.77).175... 

In brief, the use of acetonitrile as solvent and the selection of an appropriate C-5 amino protecting group and reactive promoter system are critical for achieving high a-selectivities and yields in the synthesis of sialosides. 

A practical enzymatic procedure using alcalase as biocatalyst has been developed for the synthesis of hydrophilic peptides.Alcalase is an industrial alkaline protease from Bacillus licheniformis produced by Novozymes that has been used as a detergent and for silk degumming. The major enzyme component of alcalase is the serine protease subtilisin Carlsberg, which is one of the fully characterized bacterial proteases. Alcalase has better stability and activity in polar organic solvents, such as alcohols, acetonitrile, dimethylformamide, etc., than other proteases. In addition, alcalase has wide specificity and both l- and o-amino acids that are accepted as nucleophiles at the p-1 subsite. Therefore, alcalase is a suitable biocatalyst to catalyse peptide bond formation in organic solvents under kinetic control without any racemization of the amino acids (Scheme 5.1). 

Addition of cyanide ion to a carbonyl compound leads to a cyanohydrin, a process with many applications including the synthesis of amino adds via an aminonitrile. The dired reaction between an aldehyde, KCN and NH4CI in acetonitrile leads to a mixture... 

The nitrogen atoms of heterocycles like imidazoles and triazoles have been converted into IV-nitroimide groups. The A -nitroimide (164) is synthesized from 1-amino-1,3,4-triazole (162) by IV-amination of the tertiary nitrogen with 0-picrylhydroxylamine, addition of nitric acid to give the nitrate salt (163), followed by IV-nitration with nitronium tetrafluoroborate in acetonitrile. The 1,2,3-triazole (165) and the imidazole (166) ° are synthesized in a similar way. The synthesis of IV-nitroimides has been the subject of an excellent review. ... 

Saturated 5(4//)-oxazolones are easily obtained from //-acylamino acids in the presence of a cyclization agent and have been used extensively in coupling reactions as synthetic equivalents of a-amino acids in the synthesis of peptides. In this context, tautomeric equilibrium can be a significant problem due to the racemization associated with the isomerization. For example, trifluoroacetylation of tryptophan in ether affords the 5(4//)-oxazolone 5 without racemization. However, upon dissolution in acetonitrile, 5 completely racemizes. Further, upon heating, an aqueous dioxane solution of 5 cleanly isomerizes to the isomeric 5(2//)-oxazolone 6 (Scheme 7.2). 

Primary amides can also be generated in situ from nitriles. Thus, one-pot synthesis of A -acyl-a-amino acids by Pd-catalyzed amidocarbonylation of alkyl- and arylnitriles has been developed.For example, acetonitrile was hydrolyzed to acetamide first and subjected to the reaction with cyclohexanecarbaldehyde in the same reaction vessel to give A-acetyl-2-cyclohexylglycine 13 in 92% yield (Equation (2)). This process is... 

A different route to pyrones is the preparative electrochemical oxidation of enamines in acetonitrile in the presence of tetraethylammonium perchlorate (88MI2) (Scheme 46). The synthesis of 2-pyrone derivatives has been carried out by reaction of /3-dicarbonyl compounds with methyl-a-benzoylamino-/3-dimethylaminoacrylate (96JHC751). Thiapyran derivatives can be obtained by interaction of enamines based on (/3-amino-a-cyanoacryloylmethyl)pyridinium chloride derivatives with carbon disulfide (95M711).The synthesis of pyridine derivatives based on analogous enamines has been described as well (95M711). 

Phthalimidines (isoindolin-l-ones) can be valuable intermediates for the synthesis of isoindoles and some natural products, and there has been recent interest in the development of simple methods for the direct conversion of o-phthalaldehyde into /V-substituted phthalimidines. Condensation of o-phthalaldehyde with primary aliphatic amines using acetonitrile as solvent gives disappointing yields with a-methylbenzylamine, for example, the yield of the phthalimidine 1 is only 21%. By contrast, treatment of o-phthalaldehyde with a-amino acids in hot acetonitrile gives generally excellent yields of the corresponding phthalimidines. With L-valine, for example, 2 is formed in 87% yield. 

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